4-Toluenesulfonyl chloride → 2-(4-Chlorophenyl)-5-cyclopropyl-N-methyl-6-[{2-[-2-methyloxetan-3-yl]ethyl}(methylsulfonyl)amino]-2H-indazole-3-carboxamide

Participants

Reaction Steps

2-(4-Chlorophenyl)-5-cyclopropyl-6-{[4-hydroxy-3-(hydroxymethyl)pentyl](methylsulfonyl)amino}-N-methyl-2H-indazole-3-carboxamide was prepared by alkylating 2-(4-chlorophenyl)-5-cyclopropyl-N-methyl-6-[(methylsulfonyl)amino]-2H-indazole-3-carboxamide (i) with (±)-3-(hydroxymethyl)pentane-1,4-diol (prepared from (±)-3-acetyldihydrofuran-2(3H)-one as described by T. Mitsuhiro, Yanagihara, Hiroko and Y. Sachiko, Heterocycles, 1992 33, 489-492). Then, to a solution of Compound (i) (240 mg, 0.45 mmol) in anhydrous THF (35 mL) at 0° C. under argon was added potassium tert-butoxide (60 mg, 0.53 mmol) in several portions (the reaction mixture became yellow in colour) followed by a solution of p-toluenesulfonyl chloride (95 mg, 0.50 mmol) in anhydrous THF (10 mL), which was added dropwise over 10 min. The reaction was warmed to RT and monitored by TLC/LCMS and then cooled to at 0° C. whereupon more potassium tert-butoxide (80 mg, 0.71 mmol) was added. The reaction mixture was then warmed to RT and stirred for 17 h after which time, aq. saturated ammonium chloride solution was added (20 mL) and the organics extracted into Et2O (3×100 mL), dried (MgSO4) and concentrated in vacuo. Purification by automated column chromatography (Biotage SP4, Reveleris 4 g, silica gel cartridge) eluting with EtOAc:n-heptane (gradient elution, 50% to 100% v/v) and then again by automated column chromatography (Biotage SP4, SNAP KP-C18-HS 30 g, reverse phase) eluting with ACN:water (gradient elution, 0-100% v/v) gave Compound (9) as the trans isomer (mixture of enantiomeric compounds (32) and (33)) (99 mg, 43%). 1H NMR (400 MHz, CDCl3) δ 7.70 (s, 1H), 7.56-7.48 (m, 4H), 7.37 (s, 1H), 5.88-5.82 (m, 1H), 4.62-4.47 (m, 2H), 4.24-4.15 (m, 1H), 3.62 (t, J=7.9 Hz, 2H), 3.04 (s, 3H), 2.99 (d, J=4.9 Hz, 3H), 2.67-2.53 (m, 1H), 2.45-2.33 (m, 1H), 2.06-1.82 (m, 2H), 1.39 (d, J=6.1 Hz, 1.5H), 1.36 (d, J=6.1 Hz, 1.5H), 1.17-1.04 (m, 2H), 1.04-0.93 (m, 1H), 0.66-0.54 (m, 1H). ESI-MS m/z calculated for [M+H]+: 517.2. found: 517.0.

Provenance & Evidence